DOI: https://doi.org/10.22141/2224-0713.2.96.2018.130481

Calcitonin gene-related peptide in migraine: the pathogenetic factor and therapeutic target (review)

O.Ye. Dubenko

Abstract


Migraine is a common neurological disorder that spreads in all regions in the world. Recent researches show that migraine is a complex condition involving central and peripheral trigeminovascular system, brainstem, thalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In migraine, CGRP peptide is released from trigeminal ganglia cells that cause the release of inflammatory mediators and dilatation of cranial blood vessels. The vasodilation and neurogenic inflammation further increase activation of the sensory trigeminal fibers, perpetuate the release of vasoactive peptides including CGRP, and modulate transmission of pain impulses to the brain. In addition, in acute attack, the spread of cortical depression directly activate the peripheral trigeminal nociceptors, which release nitric oxide and CGRP. CGRP is one of the most potent endogenous vasodilators, it intravenous administration induces migraine-like headache. Other function of CGRP is transmission of nociceptive information from intracranial blood vessels to the central nervous system. At present, CGRP remains the most actively evaluated target in migraine drug research. Triptans remain the gold standard of acute migraine attack therapy and inhibited release of CGRP from trigeminal sensory neurons. The paper reviews the recent findings on the development of CGRP receptor antagonists for acute treatment of episodic migraine and several monoclonal antibodies for migraine prevention. Few CGRP antagonists used small molecules and named gepants were clinically tested and demonstrated clinically efficacy but its development was discontinued due to liver toxicity. Humanized calcitonin gene-related peptide receptor monoclonal antibodies were found to be effective and safe for preventive treatment of episodic migraine and chronic migraine in randomized, double-blind, placebo-controlled trials. In episodic migraine, anti-CGRP-receptor antibody erenumab was evaluated in phase 3 trials ARISE and STRIVE. Erenumab statistically significantly reduced migraine incidence, and greater proportion of patients achieved ≥ 50% reduction of monthly migraine days compared to placebo. Fremanezumab is a humanized monoclonal antibody that selectively blocks CGRP binding to its receptor. It was effective and well-tolerated in preventing episodic migraine for 3 months of placebo-controlled phase 2 studies. In chronic migraine, the efficacy of erenumab was evaluated in 12-week trial. Results showed a significant reduction in the number of monthly migraine days and the intake of migraine-specific medications versus placebo. Humanized anti-CGRP antibody eptinezumab intravenous infusion also showed a significant reduction in heada­che impact. Anti-CGRP monoclonal antibodies can be a new generation of medication in migraine preventive treatment.

Keywords


calcitonin gene-related peptide; episodic migraine; chronic migraine; monoclonal antibodies

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